VCV002103996.29 - ClinVar

NM_005267.5(GJA8):c.137G>A (p.Gly46Glu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005267.5(GJA8):c.137G>A (p.Gly46Glu)

Variation ID: 2103996 Accession: VCV002103996.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q21.2 1: 147908092 (GRCh38) [ NCBI UCSC ] 1: 147380219 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Feb 20, 2024	Mar 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005267.5:c.137G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005258.2:p.Gly46Glu	missense
NC_000001.11:g.147908092G>A
NC_000001.10:g.147380219G>A
NG_016242.1:g.10274G>A
NG_016242.2:g.10299G>A

... more HGVS ... less HGVS

Protein change

G46E

Other names

Canonical SPDI

NC_000001.11:147908091:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GJA8		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	241	528

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cataract 1 multiple types	Likely pathogenic (1)	criteria provided, single submitter	Mar 1, 2023	RCV003029062.10
acorea,microphthalmia and cataract syndrome	Likely pathogenic (1)	no assertion criteria provided	-	RCV003388141.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Mar 01, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cataract 1 multiple types Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003315586.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 19684000‚ 21686328‚ 25260631 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly46 amino acid residue in GJA8. Other variant(s) that disrupt this residue have been observed in individuals with GJA8-related conditions (PMID: 19684000, 21686328), which suggests that this may be a clinically significant amino acid residue. This missense change has been observed in individual(s) with congenital cataracts (Invitae). ClinVar contains an entry for this variant (Variation ID: 2103996). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJA8 protein function. Experimental studies have shown that this missense change affects GJA8 function (PMID: 25260631). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 46 of the GJA8 protein (p.Gly46Glu). This variant is not present in population databases (gnomAD no frequency). (less)
Likely pathogenic (-)	no assertion criteria provided Method: research	acorea，microphthalmia and cataract syndrome (Autosomal dominant inheritance) Affected status: no Allele origin: inherited	The Key Laboratory for Human Disease Gene Study of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital Accession: SCV003920679.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Publications: PubMed (1) PubMed: 23832966 Comment: It provides a new screening target for prenatal diagnosis of familial acorea， microphthalmia and cataract syndrome Sex: mixed

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly46 amino acid residue in GJA8. Other variant(s) that disrupt this residue have been observed in individuals with GJA8-related conditions (PMID: 19684000, 21686328), which suggests that this may be a clinically significant amino acid residue. This missense change has been observed in individual(s) with congenital cataracts (Invitae). ClinVar contains an entry for this variant (Variation ID: 2103996). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJA8 protein function. Experimental studies have shown that this missense change affects GJA8 function (PMID: 25260631). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 46 of the GJA8 protein (p.Gly46Glu). This variant is not present in population databases (gnomAD no frequency).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Charge at the 46th residue of connexin 50 is crucial for the gap-junctional unitary conductance and transjunctional voltage-dependent gating.	Tong X	The Journal of physiology	2014	PMID: 25260631
Familial acorea, microphthalmia and cataract syndrome.	Kondo H	The British journal of ophthalmology	2013	PMID: 23832966
Mutational screening of six genes in Chinese patients with congenital cataract and microcornea.	Sun W	Molecular vision	2011	PMID: 21686328
A mutant connexin50 with enhanced hemichannel function leads to cell death.	Minogue PJ	Investigative ophthalmology & visual science	2009	PMID: 19684000

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005267.5(GJA8):c.137G>A (p.Gly46Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...